PROJECT SUMMARY This study aims to prove the concept and feasibility that oral administration of E+, a product formulated from a combination of generally regarded as safe compounds (GRAS), exerts therapeutic efficacy on tendinopathy. Tendinopathy is a common chronic tendon disorder that affects young athletes and 30-50% of individuals over 60 years old. It is characterized by pain, swelling, loss of function, and impaired performance and often leads to tendon rupture. There is currently no cure for tendinopathy. Spontaneous repair or treatment typically leads to scar formation, resulting in a weakened tissue with reduced function and mechanical properties that may ultimately rupture with further use. CITED2 (Cbp/p300 Interacting Transactivator with ED-rich tail 2) is a transcriptional regulator which plays a critical role in tendon stem/progenitor cell (TSPC) survival. Preliminary data strongly suggest implanting TSPCs with enhanced levels of CITED2 into a collagenase-induced tendinopathic Achilles tendon mitigated disease progression, relieved tendinopathy-related pain, and improved tendon mechanical properties. A drug that enhances CITED2 expression and is safe for a long-term use is of particular importance and is highly desired. E+ was identified based on a drug screening strategy from a pool of GRAS compounds. Our preliminary studies show E+ acts to induce the expression of CITED2, and suppresses expression of a spectrum of genes including pro-inflammatory and catabolic mediators and altered oxidative stress responses both in vitro and in vivo. Importantly, oral administration of E+ in a rat collagenase-induced tendinopathy model mitigated disease progression and relieved tendinopathy-related pain, providing evidence that led us to hypothesize that E+ treatment slows tendinopathy progression, relieves pain of tendinopathy, and improves mechanical properties of the diseased tendons. In the proposed Phase I studies, we will test this hypothesis using the overuse-induced tendinopathy model in rats by carrying out a study assessing: 1) histologic and semi-quantitative analysis of tissue and cellular morphology including number and morphology of the tenocytes, cell and collagen matrix alignment, 2) expression of tenophenotypic-related genes, 3) magnetic resonance imaging, 4) mechanical property testing, and 5) pain and other behavioral evaluations. The positive outcome will be determined quantitatively when the results of these assays show: 1) E+ treated tendons are significantly improved vs vehicle controls (p<0.05), and 2) E+ treated tendons vs nave control groups are not significantly different (p>0.05). The study will provide feasibility for the Phase II studies that are planned to provide further evidence for E+ as a drug for tendinopathy using a large animal model. Upon successful completion of Phase I and II studies, we will file an Investigational New Drug application and carry out clinical trials focusing on the most common sites of tendinopathy. These trials will contingently be carried out at Montefiore Medical Center, with an aim to market E+ as a drug for tendinopathy treatment.